Platelets or thrombocytes play a crucial role in the field of thrombosis, myocardial infarction and unstable angina: The platelet integrin receptor GPIIb/IIIa is of particular importance since it mediates platelet aggregation by binding of the bivalent plasma molecule fibrinogen. This receptor has at least two conformational states: 1) A non-activated state, which is the default state on unstimulated platelets. In this non-activated state, the receptor demonstrates a very low affinity for its ligands and is not capable of inducing platelet aggregation. 2) An activated state which is present after platelet activation, e.g. by thrombin. In this activated state GPIIb/IIIa has undergone a conformational change, which leads to high affinity binding of fibrinogen (Shatill et al., J. Biol. Chem. 1985: 260(20): 11107-11114).
Consequently the therapeutic blockade of GPIIb/IIIa is a very effective anti-platelet strategy, since it affects the final common endpoint of the platelet activation cascade. During the last years a great variety of GPIIb/IIIa-blockers have been developed. These are either chimeric mouse/human Fab-fragments of a GPIIb/IIIa-blocking monoclonal antibody (Abciximab) (Coller B., et al., J. Clin. Invest. 1983, 72: 325-338), cyclic peptides (Eptifibatide) or polycyclic synthetic peptidomimetics (e.g. Tirofiban) (Bhatt D L and Topol E J. JAMA. 2000; 284(12): 1549-58; Topol E J, et al., Lancet. 1999; 353(9148): 227-31). This therapy has been proved to be effective but there still retain some problems in this context:                especially under the therapy with Abciximab, an increased prevalence of severe thrombocytopenia is present (˜1%) (Dasgupta H., et al., Am Heart J. 2000; 140(2): 206-11).        due to the expensive production the costs of the therapy are considerably high, especially for Abciximab. (Hillegass W B, et al., Pharmacoeconomics. 2001; 19(1): 41-55).        there is an increase in bleeding complications which are especially important when GPIIb/IIIa-blockers are combined with thrombolysis.        synthetic GPIIb/IIIa-blockers which are administered orally brought disappointing results, due to their pharmacokinetic properties, particularly a rather low affinity for the receptor. (Chew D P. et al., Circulation. 2001, 103(2): 201-206).        there is evidence that GPIIb/IIIa-blocker, especially the low molecular agents, interact with the receptor after binding. This might result in a paradoxical intrinsic activating effect (Peter K., et al., Blood. 1998; 92(9): 3240-)        reversibility of the effect of Abciximab is very slow (>12 hours)        approx. 6% of the patients treated with Abciximab develop anti-human-chimeric antibodies (AHAC); 11% in case of patients treated repeatedly (Gawaz M., Therapie bei koronarer Herzerkrankung. Stuttgart, New York: Thieme, 1999).        
All GPIIb/IIIa-blockers, currently used, are binding to the activated and non-activated receptor with similar affinity. An activation specific inhibitor might offer several advantages. For example platelet adhesion would still be intact which should result in a reduction of bleeding events. Moreover interactions with the non-activated receptor would be prevented. It would be desirable to develop a smaller GPIIb/IIIa-blocking agent with an affinity similar to an antibody, which should demonstrate better pharmacokinetic properties.
Another application for an activation specific antibody would be the detection of activated platelets, which is very useful in a variety of research and diagnostic-settings.